Process for preparing 2, 4-diamino-6-(h-)-1, 3, 5-triazines



United States Patent 3,144,453 PROCESS FOR PREPARING 2,4-DIAMINO-6-(H-)-l,3,5-TRIAZINES Royal A. Cutler, Sand Lake, N.Y., assignor toSterling Drug Inc, New York, N.Y., a corporation of Delaware No Drawing.Original application Mar. 14, 1960, Ser. No. 14,559. Divided and thisapplication Oct. 18, 1960,

Ser. No. 69,785

6 Claims. (Cl. 260-2493) This invention relates to noveldisubstituted1,3,5-triazines, to methods for preparing said compounds,and to methods for converting certain of said compounds to other usefuldisubstituted-l,3,5-triazines.

One aspect of this invention relates to valuable new2,4-di-(Y-O--)-6-(H-)-1,3,5-triazines, where Y is lower alkyl or phenyl.In the free base form, these compounds have the structural formulaFormula I where Y has the same meaning indicated above. When Y is loweralkyl, I generally prefer the radicals having about 1-6 carbon atoms,for instance, methyl, ethyl, isopropyl, n-propyl, n-butyl, n-heXyl, andthe like. The 2, 4-di(lower alkoxy)-6-(H-)-l,3,5-triazines of myinvention are the free base forms represented by Formula I above and theacid-addition salts of said bases fully equivalent therewith which areobtained by reacting the bases with organic and inorganic acids, such ashydrochloric acid, phosphoric acid, methanesulfonic acid, acetic acid,and the like. The 2,4-diphenoxy-1,3,5-triazine free base form is lessbasic than the free base forms of the corresponding dialkoxy compoundsand does not dissolve readily in dilute acids.

In accordance with my invention, a convenient process for obtaining the2,4-di(Y-O)-6 (H-)-1,3,5 triazines comprises dehalogenating thecorresponding 2,4-di- (Y-O-)-6-halo-l,3,5-triazines by treatment withhydrogen in the presence of a metal hydrogenation catalyst and asuitable acid-acceptor, thus effecting the reaction represented by theequation:

/N\ N Halogen-C C-OY Hz: catalyst: H-C OO-Y I ll I II N N acid-accep torN N i O-Y OY Formula II Formula I followed, if desired, by conversion ofthe free base thus produced to an acid-addition salt. The hydrogenationcatalyst in this method can be, for example, palladium, Raney nickel,and the like. The acid-acceptor is any suitable base such as sodiumbicarbonate or triethylamine.

I have discovered that my novel 2,4-di-(Y-O-)-6- (H-)-l,3,5-triazinesare especially useful and valuable as starting materials for thepreparation of a variety of biologically active substances. Thus,ammonolysis by treatment with ammonia or a primary amine, in thepresence of an acid catalyst, replaces one or both, as desired, of theether groupings, YO-, to yield the 3,144,453 Patented Aug. 11, 1964corresponding products having in the free base forms the respectiveformulas II Iand IV below:

where Z and Z are the same or different members of the group consistingof hydrogen, alkyl, aryl, and heteryl. As ammonolysis agents there canbe used, for example: ammonia, alkylamines such as methylamine,ethylamine, isobutylamine, n-hexylamine, and the like; arylamines suchas aniline, haloanilines, alkoxyanilines, alkylmercaptoanilines,alkylsulfinylanilines, alkylsulfonylanilines,alkylmercapto-haloanilines, alkylsulfinyl-haloanilines,alkylsulfonyl-haloanilines, 4-acetylaniline, 4- sulfamylaniline(sulfanilamide), 4-biphenylamine, l-naphthylamine, and the like; andheterylamines such as aminopyridines, aminothiazoles, aminoquinolines,aminopyrimidines, and the like. When the acid used as a catalyst in theammonolysis reaction is a strong acid, for example hydrochloric acid,only a relatively small amount should be used. However, when a weakacid, such as acetic acid is employed, either large or small amounts canbe used satisfactorily, and in many instances it is convenient to employthe ammonolytic agent in the form of its acetate salt to serve both asreactant and source of catalytic acid.

Hydrolysis of my new 2,4-di-(Y-O-)-6-(H)-l,3, S-triazines replaces oneor both, as desired, of the ether groupings, YO-', by hydroxyl to yield2- (Y-O)-4- hydroxy-6-(H-)-1,3,5-triazines or 2,4-dihydroxy-1,3,S-triazine, having the respective free acid formulas V and Hydrolysis canbe effected by use of either acid or base catalyzed hydrolyticconditions.

Ammonolysis of one ether grouping and hydrolysis of the other ethergrouping in my new 2,4-di-(Y--O-)-6- (H-)-1,3,5-triazines yields thecorresponding Z-(amino or substitutedamino)-4-hydroxy-6-(H)-1,3,5-triazines having in the non-salt form thefollowing structural formula:

by Formula IV above 3 which are the joint invention of Royal A. Cutlerand Samuel Schalit and are claimed in their US. application Serial No.14,551, filed March 14, 1960. The compounds of said group within FormulaIV, which have in the free base form the structural formula I-I-C C-NHzC X-lower alkyl W3 Formula VIII wherein A is a member of the groupconsisting of hydrogen and halogen, and X is S, SO, or SO areconveniently obtained in accordance with the process of my instantinvention by interacting a 2,4-di-(YO)- 6-(H)-1,3,5-triazine withapproximately one molecular equivalent of a (lower alkyl-X-)aniline or a(lower alkyl- X-)haloaniline, and ammonolyzing the 2-(Y-O-)-4- (loweralkyl-X-phenylamino or lower alkyl-X-halophenylamino)-6-(H-) 1,3,5triazine thereby produced by treatment with ammonia in the presence ofan acid catalyst.

The 2-(ZNH) -4-hydroxy-6-(H-) -1,3,5-triazines represented in the freeacid form by Formula VII are conveniently obtained in accordance with myinvention by interacting a 2,4-di-(Y-O-)-6-(H)-1,3,5-triazine withapproximately one molecular equivalent of an ammonolyzing agent havingthe formula ZNH in the presence of an acid catalyst, and hydrolyzing the2- (Y--O-)-4-(ZNH-)-6-(I-I)-1,3,5-triazine thus obtained.

As will be appreciated, the compounds of Formula III are useful asintermediates to the compounds of Formulas IV and VII; and the compoundsof Formula V are useful as intermediates to the compound of Formula VI.

As still another aspect of the present invention, novel2-sulfanilamido-4-(Y-O) 6 (H-) 1,3,5 triazine, which can be representedin acidic form by the structural formula Formula IX are obtained byinteracting a 2,4-di-(YO)6-(H)- 1,3,5-t1iazine with approximately onemolecular equivalent of an N -alkali metal salt of sulfanilamide. Forexample, interaction of 2,4-dimethoxy-1,3,5-triazine with approximatelyone molecular equivalent of the N -sodium salt of sulfanilamide yields2-sulfanilamido-4-methoxy- 1,3,5-triazine. Like the parent compoundsulfanilamide, the acid forms (Formula IX) of these 2-sulfanilamido-4-(YO-)-6-(H--)-1,3,5-triazines react with bases, for instance alkalimetal hydroxides such as sodium hydroxide, to form salts, owing to theacidity of the N -hydrogen. The new 2-sulfanilarnido-4-(YO)-6-(H)-1,3,5-triazines of my invention are the free acid forms of Formula IXabove and the salts thereof, the salts being the full equivalent of theacid forms. These compounds of my invention have antibacterialproperties and are useful as antibacterial agents.

My invention is illustrated by the following examples without, however,being limitedthereto.

EXAMPLE 1 2,4-Dimethoxy-1,3,5-Triazine A mixture of 87.7 g. of2,4-dimethoxy-6-chloro-1,3,5- triazine, 45 g. of sodium bicarbonate, 550ml. of methanol, 150 ml. of water, and 5 g. of palladium-on-charcoalcatalyst (containing 0.5 g. of palladium chloride) was hydrogenated atan initial hydrogen pressure of 525 pounds per square inch at roomtemperature (about 25 C.) for four hours, with shaking. The finalhydrogen pressure was 450 pounds per square inch. The catalyst was thenremoved by filtration, and the filtrate was evaporated under reducedpressure on a warm water-bath to yield a semi-solid residue. Thisresidue was dissolved in hot petroleum ether and the resulting solutionwas filtered while hot. The filtrate was cooled and the solid whichseparated from solution was collected on a filter. There was thusobtained 37.3 g. of solid which was recrystallized from petroleum etherto yield 25.1 g. of white solid. This product, which melted at 58-60 C.,was 2,4-dimethoxy-1,3,5-triazine (Formula I:

Y=CH -O) having the molecular formula C H N O EXAMPLE 22,4-Dz'meth0xy-1,3,5-Triazilze Proceeding in a manner similar to thatdescribed in Example 1, a mixture of 80.1 g of6-chloro-2,4-dimethoxy-1,3,5-triazine, 43 g. of sodium bicarbonate, 500ml. of methanol, ml. of water, and 5 g. of palladium-oncharcoal catalyst(containing 0.5 g. of palladium chloride) was hydrogenated at an initialhydrogen pressure of 535 pounds per square inch at room temperature forseven hours to yield 47.3 g. of white solid melting at 5559 C. Thisproduct which was crude 2,4-dirnethoxy- 1,3,5-triazine, wasrecrystallized from petroleum ether to yield 38.1 g. of the purifiedcompound.

EXAMPLE 3 2,4-Dieth0xy-1,3,5-Triazine A mixture of 3.29 g. of6-chloro-2,4-diethoxy-1,3,5- triazine, 1.36 g. of sodium bicarbonateslurried in 50 ml. of water, 200 g. of isopropyl alcohol, 0.2 g. ofpalladium chloride, and 2 g. of charcoal was hydrogenated at an initialhydrogen pressure of 46 pounds per square inch at room temperature forfour hours, with shaking. The total drop in hydrogen pressure was 10pounds per square inch, virtually all of this drop having occurredwithin the first two hours. The catalyst was then removed by filtration,and the colorless filtrate was evapo' rated to dryness under reducedpressure on a warm water bath. The white solid obtained as a residue wasslurried in water to remove sodium chloride, and the slurry wasfiltered. The solid thus collected was washed with water and dried.There was thus obtained 1.2 g. of white crystalline solid which wasrecrystallized from petroleum ether with charcoaling to yield 0.78 g. ofglistening white needles which melted at 49-51 C. This product was2,4-diethoxy-1,3,5-triazine, (Formula I: Y=C H O-), having the molecularformula CqHnNaOz.

EMMPLE 4 2,4-Diphen0xy-1,3,5-Triazirze A mixture of 45 g. of6-chloro-2,4-diphenoxy-1,3,5- triazine dissolved in 400 ml. of dioxane,12.6 g. of sodium bicarbonate slurried in 50 ml. of water, 1 g. ofpalladium chloride, and 10 g. of charcoal was hydrogenated at an initialhydrogen pressure of 550 pounds per square inch at 28 C. for three andthree-quarters hours, with shaking. The catalyst was then removed byfiltration, and the filtrate was evaporated to dryness under reducedpressure on a warm water-bath. The solid residue thus obtained wasground in a mortar, washed with water, and dried. The resulting solid,which weighed 39 g., was recrystallized from 400 ml. of petroleum ether,with charcoaling. There was obtained in this manner 28 g. of White solidwhich melted at -107 C. after softening at 102 C. This product was2,4-diphenoxy-1,3,5-

triazine (Formula 1:

EXAMPLE 2-Meth0xy-4- (4-Chlorophenylamin0) -1,3,5-Triazine of2,4-dirnetl1oxy-1,3,5-triazine, 9.1 g. of 4-ch1oroaniline, and 4.25 g.(4.4 ml.) of acetic acid was heated at 120 C. on an oil bath for aboutone hour. The reaction mixture was removed from the oil bath and after afew minutes was cooled and poured into ice water. The solid whichseparated from solution was collected on a filter and Washed with water.The solid was then dissolved in hot ethanol, and after addingdecolorizing charcoal the solution was filtered while hot. The filtratewas chilled and the crystalline solid which separated from solution wascollected on a filter. This product, which weighed 5.7 g. and melted at168l71 C., was 2-methoxy-4-(4-chlorophenylamino) 1,3,5-triazine, havingthe structural formula A mixture of g.

EXAMPLE 6 2-Phen0xy-4- (4-Methylmercaptophenylamino) J ,3 ,5 -Triazine Amixture of 5 g. of 2,4-diphenoxy-1,3,5-triazine, 3.32 g. of4-methylmercaptoaniline hydrochloride, and 1.55 g. of fused sodiumacetate was heated in a 25 ml. round bottomed flask in an oil bath at123133 C. for one hour. Initially, an exothermic reaction occurred asindicated by a 10 C. rise in temperature of the reaction mixture abovethe bath temperature, and then the temperature of the reaction mixturegradually fell back to that of the bath. A distinct odor of phenolbecame evident as the reaction mixture gradually liquefied and thenlater partially solidified. At the end of the reaction period, water wasadded to the pasty product, and the mixture was allowed to standovernight, during which time the pasty mass crystallized. The mixturewas filtered and the tan solid thus collected was washed with water anddried to give 11.5 g. of product. This solid was purified by dissolvingit in 150 ml. of nitromethane, filtering the resulting solution toremove a small amount of undissolved material, and chilling the filtrateto cause separation of 1.5 g. of solid melting at 162-164 C.Recrystallization of this solid from 20 ml. of acetonitrile yielded awhite solid which melted at l6l162 C. This product was2-phenoxy-4-(4-methylmercaptophenylamino)-1,3,5-triazine, having thestructural formula EXAMPLE 7 2-Amin0-4- (4-Chlorophenylamino)-1,3,5-Triazine A mixture of 1.2 g. of 2-methoxy-4-(4chlorophenylamino)-1,3,5-triazine and 2.4 g. of ammonium acetate was heated for twohours at l35-140 C. During this heating period, the mixture graduallybecame pasty, then liquefied, and finally became substantiallysolidified.

This white product was cooled and slurried in water, and the mixture wasfiltered. The solid thus collected was washed with water and dried. Theresulting product, which weighed 0.97 g., was recrystallized fromdioxane to yield a white crystalline solid which melted at 262- 264 C.This product was 2amino4-(4-chlorophenylamino)-l,3,5-triazine, havingthe structural formula This product is a known compound useful as adiuretic agent, particularly in the form of its hydrochloride.

EXAMPLE 8 2-Hydr0xy-4-(4-Chlorophenylamino) -1,3,5-Tr1'azine A mixtureof 8.0 g. of 2-methoxy-4-(4-chlorophenylamino)-1,3,5-triazine, 50 ml. ofwater, and 8 m1. of 10 percent aqueous sodium hydroxide solution washeated to reflux temperature, 10 ml. more of 10 percent aqueous sodiumhydroxide solution was added, and heating was continued at refluxtemperature. Almost all of the solid in the mixture dissolved, and theresulting solution was filtered. The filtrate was heated to redissolvesome solid which had separated as the solution cooled, and thensuificient acetic acid was added to make the solution acidic. Theacidified solution was cooled and the solid which separated fromsolution was collected on a filter. There was thus obtained 5.0 g. ofthe diuretic compound 2-hydroxy-4-(4-chlorophenylamino)1,3,5-triazine,having the structural formula which melted at 295-297 C. withdecomposition.

EXAMPLE 9 2-Amin0-4- (4-L0wer Alkylmercaplophenylamino) 1,3,5-TriazinesThe above-designated products, which are diuretic agents, are preparedas follows. Using the procedure described above in Example 5, butsubstituting 11.1 g. of 4-ethylmercaptoaniline for the 4-chloroaniline,there is obtained 2-rnethoxy-4-(4-ethylmercaptophenylamino)-1,3,5-triazine. Ammonolysis of this compound by treatment with ammoniumacetate by a procedure similar to that described above in Example 7,there is obtained 2-amino-4-(4 ethylmercaptophenylamino) 1,3,5 triazine,which melts at 175-177" C.

Similarly, use of 11.9 g. of 4-n-propylrnercaptoaniline in the firststep above yields2-methoxy-4-(4-n-propyhnercaptophenylamino)-l,3,5-triazine, which isammonolyzed by ammonium acetate to yield2-amino-4-(4-n-propylmercaptophenylarnino)- 1,3,5-triazine, M.P. l57l58C.; use of 12.9 g. of 4-n-butylmercaptoaniline in the first step yields2-methoxy-4-(4-n-butylmercaptophenylamino)-1,3, S-triazine, which isammonolyzed by ammonium acetate to yield2-amino-4-(4-n-butylmercaptophenylamino)-l,3, S-triazine, M.P. 161-l62C.

2 amino 4-(4-rnethylmercaptophenylarnino)-1,3,5- triazine was preparedas follows: A mixture of 0.5 g. of 2-(4-methylrnercaptophenylamino)-4phenoxy 1,3,5- triazine and 0.55 g. of ammonium acetate was heated bymeans of an oil bath at -140 C. for two hours. The reaction mixturegradually became liquid and the odor of phenol was plainly evident.After cooling, the solid re- EXAMPLE 10 2-A m1'120-4-(4-Sulfamylphenylamino) -1,3,5-Triazine Proceeding in the mannerdescribed above in Example 5, but substituting 12.2 g. ofp-sulfamylaniline (sulfanilamide) for the 4-chloroaniline, there isobtained as the product2-methoxy-4-(4-sulfamylphenylamino)-1,3,5-triazine. By ammonolysis ofthis compound by treatment with ammonium acetate by a procedure similarto that described above in Example 7, there is obtained Z-amino-4-(4-sulfamylphenylamino)-l,3,5-triazine, M.P. 283284 C. This is a knowncompound having diuretic properties.

EXAMPLE 11 2,4-Dilzydroxy-J,3,5-Triazi/ze Hydrolysis of2,4-dimethoxy-1,3,5-triazine by heating it with concentratedhydrochloric acid for a few minutes, yields2,4-dihydroxy-1,3,5-triazine,

H M.P. 272 C., a known compound of biological interest. EXAMPLE 122-Sulfa1zilamid0-4-Metlz0xy-1,3,5-Triazine A mixture of 14.1 g. of2,4-dimethoxy-1,3,5-triazine, 17.2 g. of sulfanilamide, 2.53 g. ofsodium, and 100 ml. of methanol was refluxed on a steam bath fortwenty-six hours, moisture being excluded by use of a drying tube. Thereaction mixture Was then evaporated under reduced pressure on a warmwater bath to yield as a residue 34 g. of white solid. This solid wasdissolved in 400 ml. of water to form a cloudy solution which wasalkaline to pH indicator paper. The solution was made slightly acidic bygradually adding dilute acetic acid to it with stirring. The white solidwhich separated from solution was collected on a filter, washed withwater, and dried. This solid, which weighed 24 g., was dissolved in 200ml. of hot acetontrile and the resulting solution was filtered while hotafter addition of decolorizing charcoal. The filtrate was chilledovernight and then the solid which had separated from solution wascollected on a filter, washed with a small amount of acetonitrile, anddried. There was thus obtained 18.5 g. of white crystalline solid whichmelted at 196-197 C. with decomposition. This product was2-sulfanilamido-4-methoxy-1,3,5-triazine, having the structural formulaagent. It was soluble in a mixture of dilute sodium hydroxide and water(in proportion of 0.36 ml. of 0.5 N

aqueous sodium hydroxide solution and 0.14 ml. of water) to the extentof 10 percent; the pH of a 1 percent solution in this dilute alkalibeing 12.0. When an alkaline solution thus obtained was adjusted to pH 7by addition of 0.1 N hydrochloric acid, no precipitate was formed.

EXAMPLE 13 2-Sulfmzilamia'0-4-Elh0xy-1 ,3,5-Triazine Proceeding in themanner described in Example 12, but substituting 16.9 g. of2,4-diethoxy-1,3,5-triazine for the 2,4-dimethoxy-1,3,5-triazine and 120ml. of absolute ethanol for the methanol, there is obtained as theproduct 2-sulfanilamido-4-ethoxy1,3,5-triazine, melting at 210212 C. andhaving the structural formula This compound is also produced byalcoholysis of 2- sulfanilamido-4methoxy-1,3,5-triazine with ethanol inthe presence of sodium ethoxide, in the following manner: To 50 ml. ofanhydrous ethyl alcohol in a ml. round bottomed flask fitted with areflux condenser, there was added 0.08 g. of sodium. After all of thesodium had reacted, 0.72 g. of 2-sulfanilamido-4-methoxy-1,3,5-triazinewas added and the resulting solution was heated at reflux temperaturefor one and one-half hours on a steam bath. Evaporation of the ethylalcohol from the reaction mixture gave a white residue, which was thendissolved in 30 ml. of water. The resulting solution was made slightlyacidic by addition of dilute acetic acid. The white solid thusprecipitated was collected on a filter, washed with water, and dried togive 0.42 g. of white solid. Recrystallization of this solid from 8 ml.of acetonitrile yielded 0.31 g. of white solid which melted at 2l0212 C.This product was 2-sulfanilamido-4ethoxy- 1,3,5-triazine.

EXAMPLE 14 Z-Sulfanilamido-4-Plzenoxy-1,3,5-Triazi:ze

A solution of sodium phenoxide was prepared by dissolving 9.4 g. ofphenol in 100 ml. of anhydrous dioxane and adding 1.15 g. of sodium.When the sodium had disappeared, 8.6 g. of sulfanilamide was addedfollowed by the addition of a solution of 13.3 g. of 2,4-diphenoxy-1,3,5-triazine in 100 ml. of anhydrous dioxane. The resulting slurry wasstirred and refluxed (while protecting the reaction mixture frommoisture by means of a drying tube) for twelve hours, and then theexcess dioxane was removed by distillation under reduced pressure. Thesolid residue which remained was dissolved in 250 ml. of water and thedark solution thus obtained was filtered after addition of decolorizingcharcoal. On making the filtrate slightly acid with dilute acetic acid,a tan solid was precipitated from solution. This solid was collected ona filter, washed with water, and dried. There was thus obtained 18.5 g.of solid which was purified by dissolving it in 250 ml. of hotacetonitrile, filtering the hot solution after addition of decolorizingcharcoal, and cooling the filtrate. The solid which separated fromsolution was collected on a filter and dried. There was thus obtained 4g. of white fluffy needles. This product was2-sulfanilamide-4-phenoxy-l,3,5-triazine, having the structural formulaThis product melted completely when a melting point capillary tubecontaining a sample of it was dropped into a bath preheated to 275 C.When the temperature of another sample of the product was raised slowlyit sintered and shrank at temperatures below 275 C. and appeared 5 tochange crystalline form, but it failed to melt even when the bath wasraised to 300 C.

This application is a division of my copending application, Serial No.14,550, filed March 14, 1960, now

wherein A is a member of the group consisting of hydrogen and halogen,and X is a member of the group 25 consisting of S, -SO-, and -SO whichcomprises ammonolyzing a compound of the formula where Y is a member ofthe group consisting of lower 40 alkyl and phenyl by treatment withammonium acetate.

2. The process for preparing a 2-(H N)-4-[4-(loweralkylmercapto)phenylamino]-6-(H) 1,3,5 triazine which comprisesammonolyzing a 2-(lower alkoxy)-4-[4- (loweralkylmercapto)phenylamino]-6-(H)-1,3,5 triazine with ammonium acetate.

3. The process for preparing 2-amino-4(4-ethylmercaptophenylamino)-1,3,5-triazine which comprises ammonolyzing2-methoxy-4-(ethylmarcaptophenylamino)-1, 3,5-triazine by heating withammonium acetate.

4. The process for preparing2-amino-4-(4-n-propylmereaptophenylaminno)-l,3,5-triazine whichcomprises ammonolyzing 2methoxy-4-(n-propylmercaptophenylamino)-1,3,5-triazine by heating withammonium acetate.

5. The process for preparing2-an1ino-4-(4-n-butylmercaptophenylarnino)-1,3,5-triazine whichcomprises ammonolyzing 2-methoxy-4-(n-butylmercaptophenylamino)-1,3,5-triazine by heating with ammonium acetate.

6. The process for preparing2-amino-4-(4-methylmercaptophenylamino)-1,3,5-triazine which comprisesammonolyzing 2 (4-methylmercaptophenylamino)-4-phenoxy-1,3,5-triazine byheating with ammonium acetate.

References Cited in the file of this patent UNITED STATES PATENTS Mackayet a1 Ian. 18, 1949 Sherred Nov. 13, 1956 OTHER REFERENCES

1. THE PROCESS FOR PREPARING A COMPOUND OF THE FORMULA